Cardiovascular disease is the nation's leading cause of death, claiming a life every 33 seconds, 2600 lives each day, and nearly one million lives each year. For the majority of patients with any type of significantly advanced heart failure, the common, final clinical scenario is of a severely limited quality of life associated with a significant risk of death. The hypothesis behind the proposed projects is that stem cell therapy will benefit patients with varying degrees of heart failure. To date, the cummulative data from our studies and several others demonstrate that stem cell injections appear to be safe and possibly effective in at least some patients with heart failure. Our research consortium has conducted many studies (both pre-clinical and clinical) in this area of research and is currently enrolling patients in an FDA-approved Phase I clinical trial of transendocardial injections of autologous bone marrow-derived mononuclear cells for treatment of patients with advanced heart failure. In this application, we propose 2 potential protocols for the network. Protocol 1 allows us to continue our present trial with a Phase II trial that will also address an important question that remains unanswered: What is the ideal number of cells for transplant? (i.e.: Would 100,000,000 cells be more beneficial than the 30,000,000 we are currently using?) Protocol 2 focuses on the immediate postinfarct period and uses a specific type of stem cell, the Stro bright or mesenchymal precursor cell (MPC). All cells will be injected transendocardially and guided by electromechanical mapping into areas of viable myocardium. Safety of the cell delivery process will be assessed periprocedurely with Holter monitoring, and long-term safety will be assessed clinically for at least 3 years with imaging studies and catheter evaluations. Efficacy will be assessed primarily on the basis of imaging studies (echo, angio, MRI, SPECT, X-ray) and EKG, 24hr Holter monitoring, treadmill with MVO2, and lab work. We have now completed two pre-clinical studies using mesenchymal cell injections in canine models of chronic ischemia and acute myocardial infarction (AMI). Both studies demonstrated that mesenchymal cells injected by the transendocardial route differentiated into smooth muscle cells and endothelial cells, and resulted in increased vascularity and improved cardiac function. If proven safe and effective in FDA-approved clinical trials, these new therapies could extend the lives and improve the quality of life for almost 1 million people each year in the U.S. alone. (End of Abstract)